Antidepressant compositions and methods employing 4-arylbicyclo(2.2.2)octyl urethans



United States Patent 3,507,957 ANTIDEPRESSANT COMPOSITIONS AND METH- ODS EMPLOYING 4-ARYLBICYCLO[2.2.2]OCTYL URETHANS Paul E. Aldrich, Sharpley, DeL, assignor to E. I. du Pont de Nemours and Company, a corporation of Delaware No Drawing. Filed Jan. 12, 1968, Ser. No. 697,302 Int. Cl. A61k 27/00 US. Cl. 424-203 8 Claims ABSTRACT OF THE DISCLOSURE This invention teaches the preparation of 4-arylbicyclo [2.2.2]oct-1-yl urethans and methods of using and formulating the same as antidepressant agents.

Representative of the compounds within the scope of this invention are ethyl N-4-phenylbicyclo[2.2.2]oct-2-enl-yl urethan, propyl N-4-(o-tolyl)bicyclo[2.2.2]octane- 1-yl urethan, methyl N-4-(4-pyridyl)bicyclo[2.2.2]octane-l-yl urethan and propyl N-4-[4-(3-fluoropyridyl)] bicyclo[2.2.2]oct-2-ene-1-yl urethan.

Background of the invention This invention relates to methods of using 4-arylbicyclo [2.2.2]oct-1-yl urethans as pharmaceutical agents. More particularly, this invention relates to said 4-aryl-bicyclo [2.2.2]oct-1-yl urethans which can be used as antidepressant agents.

Before the late 1950s no adequate pharmaceutical agent was known which could be used for the treatment of depression, and the medical arts had to rely on psychotherapy for treating mild depressions and electroconvulsive therapy to counteract severe depressions.

Then, in the late 1950s, the first truly effective pharmacological agents useful for treating various depressive syndromes were developed. These agents were lumped together as a class known as monamine oxidase (MAO) inhibitors based on their ability to inhibit the metabolic oxidative deamination of naturally occurring amines such as dopamine and tyramine. These MAO inhibitors comprise a heterogeneous group of drugs having in common this ability to inhibit the metabolic oxidative deamination of naturally occurring amines. I

A later development in the treatment of depression was the discovery that dibenzazepine derivatives could be used to treat depressive syndromes. These agents are thought of as the successors to the MAO inhibitors and although theyre mode of action is not well understood, they are effective antidepressants.

The discovery of the above described agents as useful therapeutic agents for treating depressive syndromes has presented psychotherapy with a useful tool that can and has been advantageously used in the management of depression.

There is however, a continuing need for new agents in this field. It is in this field of antidepressive agents that the compounds of this invention are useful and can conribute to the progress of the medical arts.

Summary of the invention I have discovered that the N-4-arylbicyclo[2.2.2]oct-1- yl urethans are useful as antidepressant agents. For the purposes of this description, the term N-4-arylbicyclo [2.2.2]oct-l-yl urethans includes the following types of compounds:

N-4-phenylbicyclo[2.2.2]oct-2-en-1-yl urthans, N-4- (substituted-phenyl)bicyclo [2.2.2] oct-2-en-1-yl urethans, N-4-phenylbicyclo[2.2.2]octane-1-yl urethans, N-4-(substituted-phenyl)bicyclo[2.2.2]octane-1-yl urethans, N-4- pyridylbicyclo[2.2.2]oct-2-en-1-yl urethans, and N-4-(substituted-pyridyl)bicyclo[2.2.2]oct-2-en-1-yl urethans.

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The compounds for use according to the method of this invention are presented by the following formulae:

-NHCOOR where R is alkyl of 1 through 8 carbons, ethyl pyrrolidinyl or phenyl; and R and R are hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl group has 1 through 4 and preferably 1 through 2 carbons, cyano, alkoxy of 1 through 4 and preferably 1 through 2 carbons, alkoxycarbonyl where the alkyl group has 1 through 2 carbons, or trifluoromethyl;

-NHCOOR where R is alkyl of 1 through 8 carbons, ethylpyrrolidinyl or phenyl; and R and R are hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl group has 1 through 4 and preferably 1 through 2 carbons, cyano, alkoxy of 1 through 4 and preferably 1 through 2 carbons, alkoxycarbonyl where the alkyl group has 1 through 2 carbons, or trifluoro- (III) where R is alkyl containing from 1 through 8 carbons, ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl contains from 1 through 4 carbons, cyano, alkoxy containing from 1 through 4 carbons, alkoxycarbonyl where the alkyl contains from 1 through 2 carbons, or trifluoromethyl.

-NHCOOR where R is alkyl containing from I through 8 carbons, ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl contains from 1 through 4 carbons, cyano, alkoxy containing from 1 through 4 carbons, alkoxy carbonyl where the alkyl contains from 1 through 2 carbons or trifluoromethyl.

Salts of the above compounds with non-toxic anions are included within the scope of this invention where such salt formation is possible. Representative acids from which said anions are derived include hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, citric acid and carbonic acid.

Preferred compounds of this invention are those of Formulae I-IV in which R is as defined above and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialklyamino where each alkyl contains from 1 through 2 carbons, alkoxycarbonyl where the alkyl contains from 1 through 2 carbons, and trifiuoromethyl.

Particularly preferred of the compounds are those where R is alkyl containing from 1 through 4 carbons and R is hydrogen.

Also included within the scope of this invention is the method of producing an antidepressant effect in warmblooded animals which comprises administering to said warmblooded animal one or more compounds of Formulae I through IV in admixture with other pharmaceutically useful antidepressant compounds.

Description of the invention The compounds of Formulae I through IV can be prepared by converting a 4-arylbicyclo[2.2.2]oct-2-en-lcarboxylic acid to the corresponding 4-arylbicyclo[2.2.2]- oct-2-en-1-yl urethane by a modified Curtius reaction [J. Org. Chem. 26, 3511 (1961)] in which a mixed anhydride of the acid is formed with ethyl chloroformate and then treated with sodium azide to form the acid azide. This is heated in toluene to cause rearrangement to the isocyanate, which is treated with an alcohol to form a urethane of this invention.

The 4-arylbicyclo[2.2.2]oct 2 en 1 carboxylic acid starting materials for the above described reaction can be prepared generally as follows.

A mixture of 6-aryl-a-pyrone -3carboxylic acid ethyl ester and benzene is mixed with ethylene in a suitable pressure vessel which is then pressured up to 1000 atmospheres at a temperature of under 200 C. The system pressure is increased to up to 3000 atmospheres with ethylene and the elevated temperature is maintained for up to 13 hours. From time to time during this reaction phase, it is necessary to repressure the system with ethylene to maintain the proper pressure.

The pressure vessel is then cooled and the contents discharged, diluted with ethanol and filtered. The alcohol and benzene are distilled off, leaving ethyl 4-arylbicyclo[2.2.2]oct-2-en-l-carboxylate.

The ethyl 6-aryl-a-pyrone-3-carboxylate can be obtained by the method of Kochetkov et al., J. Gen Chem. USSR (English Translation) 28, 1562 (1958).

The ethyl 4-arylbicyclo[2.2.2]oct-2-ene-l-carboxylate is saponified by heating with aqueous sodium hydroxide until dissolved and then acidifying to precipitate the acid. The acid is filtered off, washed and dried. Alternatively saponification can be effected by heating with sodium hydroxide in diethylene glycol at 160 C. for two hours. The ethyl 4-(4-pyridyl)bicyclo[2.2.2]oct-2-ene-l-carboxylates are preferably hydrolyzed by refluxing with 6N HCl for 16 hours and then adjusting the pH to the isoelectric point with base.

A number of 4-pyridylbicyolo[2.2.2]oct-Z-ene-l-carboxylic acids are too insoluble to be converted to the isocyanate by the modified Curtius reaction outlined above. When this problem arises, the difficulty can be overcome by using the classical Curtius reaction in which the acid chloride is prepared and then treated wtih sodium axide to form the acid azide. The acid azide is refluxed with an alcohol and a base such as triethylamine to an alkyl urethan. In addition to the above descriptions of the preparation of the compounds of this invention, a better understanding of my invention will be gained by reference to the following examples illustrating the preparation of representative com-pounds of this invention.

Example 1 A solution of 0.11.5 mole of triethylamine in 100 ml. of acetone is added to a stirred mixture of 0.10 mole of 4-(3-pyridyl)bicyclo[2.2.2]oct-2-en-1-carboxylic acid and 300 ml. of acetone. This solution is cooled to 5 to C. and a solution of 0.11 mole of ethyl chloroformate in 50 ml. of acetone is added dropwise, with cooling, at a rate such that the temperature does not rise above 0 C. When the addition is complete, stirring is continued for 30 minutes, and then a solution of 0.15 mole of sodium azide in 30 ml. of water is added dropwise at to 0 C.

After addition is completed, stirring is continued for 1 hour. The cold solution is diluted with ice water and extracted with toluene. The toluene solution is dried with anhydrous magnesium sulfate, filtered, and heated on a steam bath until the evolution of nitrogen is complete. Then, ml. of butanol and 0.5 g. of "Dabco (1,4-diazabicyclo [2.2.2]octane) are added and the mixture is heated at reflux for 30 minutes. Concentration of the reaction mixture yields a residue of butyl N-4-(3-pyridyl)bicyclo[2.2.2]oct-2-en-1-yl urethan.

Example 2 A solution of 0.115 mole of triethylamine in 100 ml. of acetone is added to a stirred mixture of 0.10 mole of 4-(2-pyridyl)bicyclo[2.2.2]oct-2-en-1-carboxylic acid and 300 ml. of acetone. This solution is cooled to -5 to 0 C.

and a solution of 0.11 mole of ethyl chloroformate in 50 ml. of acetone is added dropwise, with cooling, at a rate such that the temperature does not rise above .0 C. When the addition is complete, stirring is contin'ued for 30 minutes, and then a solution of 0.15 mole of sodium azide in 30 ml. of water is added dropwise at 5 to 0 C. After addition is complete, stirring is continued for 1 hour. The cold solution is diluted with ice water and extracted with toluene. The toluene solution is dried with anhydrous magnesium sulfate, filtered, and heated on a steam bath until the evolution of nitrogen is complete. Then, 100 ml. of 2-propanol and 0.5 g. of Dabco (1,4-diazabicyc1o[2.2.2]octane) are added and the mixture is heated at reflux for 30 minutes. Concentration of the reaction mixture yields a residue of 2-propyl N-4-(2-pyridyl)bicyclo[2.2.2]oct-2-en-1-yl urethan.

Example 3 A solution of 0.115 mole of triethylamine in 100 ml. of acetone is added to a stirred mixture of 0.10 mole of 4- [2- 5-ethylpyridyl) ]bicyclo [2.2.2] oct-2-enl-carbloxfylic acid and 300 ml. of acetone. This solution is cooled to 5 to 0 C. and a solution of 0.11 mole of ethyl chloroformate in 50 ml. of acetone is added dropwise, with cooling, at a rate such that the temperature does not rise above 0 C. When the addition is complete, stirring is continued for 30 min., and then a solution 0.15 mole sodium azide in 30 ml. of water is added dropwise at 5 to 0 C. After addition is complete, stirring is continued for 1 hour. The cold solution is diluted with ice water and extracted with toluene. The toluene solution is dried with anhydrous magnesium sulfate, filtered, and heated on a steam bath until the evolution of nitrogen is complete. Then, 100 ml. of n-propanol and 0.5 g. of Dabco (1,4-diazabicyclo[2.2.2]octane) are added and the mixture is heated at reflux for 30 min. Concentration of the reaction mixture yields a residue of n-propyl N-4-[2-(5- ethylpyridyl) ]bicyclo [2.2.2]oct-2-en-1-yl urethan.

EXAMPLE 4 A solution of 0.115 mole of triethylamine in 100 ml. of acetone is added to a stirred mixture of 0.10 mole of 4-[ 5-(3-chloropyridyl)]bicyclo[2.2.2]oct 2 en-l-carboxylic acid and 300 ml. of acetone. This solution is cooled to 5 to 0 C. and a solution of 0.11 mole of ethyl chloroformate in 50 ml. of acetone is added dropwise, with cooling, at a rate such that the temperature does not rise above 0 C. When the addition is complete, stirring is continued for 30 min., and then a solution of 0.15 mole of sodium azide in 30 ml. of Water is added dropwise at 5 to 0 C. After addition is complete, stirring is continued for 1 hour. The cold solution is diluted with ice water and extracted with toluene. The toluene solution is dried with anhydrous magnesium sulfate, filtered and heated on a steam bath until the evolution of nitrogen is complete. Then, 100 ml. of methanol and 0.5 g. of Dabco (1,4-diazabicyclo[2.2.2]octane) are added and the mixture is heated at reflux for 30 min. Concentration of the reaction mixture yields a residue of methyl N-4- [5-(3-chloropyridyl)]-bicyclo[2.2.2]oct 2 en-l-yl urethan. Example 5 A solution of 0.115 mole of triethylamine in 100 ml. of acetone is added to a stirred mixture of 0.10 mole of 4-(3-methyl 4 pyridyl)bicyclo[2.2.2]oct-2-en-1-carboxylic acid and 300 ml. of acetone. This solution is cooled to 5 to C. and a solution of 0.11 mole of ethyl chloroformate in 50 ml. of acetone is added dropwise, with cooling, at a rate such that the temperature doesnot rise above 0 C. When the addition is complete, stirring is continued for 30 min., andthen a solution of 0.15 mole of sodium azide in 30 ml. of water is added dropwise at to 0 C. After addition is complete, stirring is continued for 1 hour. The cold solution is diluted with ice water and extracted with toluene. The

toluene solution is dried with anhydrous magnesiunrsulfate, filtered and heated on a steam bath until the evolution of nitrogen is complete. Then, 100 ml. of methanol and 0.5 g. of Dabco (1,4-diazabicyclo [2.2.2]octane) are added and the mixture is heated at reflux for 30 min.

ethyl chloroformate in 50 ml. of acetone is added dropwise, with cooling, at a rate such that the temperature does not rise above 0 C. When the addition is complete, stirring is continued for 30 min., and then a solution of 0.15 mole of sodium azide in 30 ml. of water is added dropwise at -5 to 0 C. After addition is complete, stirring is continued for 1 hour. The cold solution is diluted with ice water and extracted with toluene. The toluene solution is dried with anhydrous magnesium sulfate, filtered and heated on a steam bath until the evolution of nitrogen is complete. Then, 100 ml. of methanol and 0.5 g. of Dabco (1,4-diazabicyclo[2.2.2]octane) are added and the mixture is heated at reflux for 30 min. Concentration of the reaction mixture yields a residue of methyl N-4-[4-(2-trifluoromethylpyridyl)]bicyclo [2.2.2]oct-2-en-1-yl urethan.

Example 9 of acetone is added to a stirred mixture of 0.10 mole of ,4 [2 (3 methoxypyridyl)]bicyclo[2.2.2]oct 2 en-1- Concentration of the reaction mixture yields a residue of methyl N-4-(3-methyl 4 pyridyl)-'bicy Q[2.2.21o t 2- en-l-yl urethan.

Example 6' V A solution of 0.115 mole of triethylamine in 100 ml. of acetone is added to a stirred mixture of 0.10 mole of 4-[4-(3-fluoropyridyl)]bicyclo[2.2.2]oct-2-en 1 carboxylic acid and 300 ml. of acetone. This solution is cooled to 5 to 0 C. and a solution of 0;11 mole of ethyl chloroformate in 50 ml. of acetone is added dropwise, withcooling, at a rate such that the temperature does not rise above 0 C. When the addition is complete, stirring is continued for 30 min., and then a solution of 0.15 mole of sodium azide in 30 ml. of water is added dropwise at 5 to 0 C. After addition is complete, stirring is continued for 1 hour. The cold solution is diluted with ice water and extracted with toluene. The toluene solution is dried'with anhydrous magnesium sulfate, filtered, and heated on a steam bath until the evolution of nitrogen is complete. Then, 100 ml. of methanol and 0.5 g .of Dabco (1,4-diazabicyclo[2.2.2]octane) areadded and the mixture is heated at reflux for 30 min.

Concentration of the reaction mixture yields a residue.

of methyl N-4-[4-(3-fluoropyridyl)]-bicyclo[2.2.2]oct-2- en-l-yl urethan. f Example 7 A solution of 0.115 mole of triethylamine in 100ml, of acetone is added to a stirred mixture of 0.10 mole of 0.15 mole of sodium az'ide'in 30: ml. of water is added 4-[4-(3-bromopyridyl)]bicyclo[2.2.2]oct 2 en-1carboxylic acid and 300 ml. of acetone. This. solution;- is cooled to 5 to 0 C. and a solution of 0.11 mole'of-f ethyl chloroformate in 50 ml. of acetone is addeddrop wise, with cooling, at a rate such that the 'temperatur e" does not rise above 0 C. When the additioniscomplete; L

stirring is continued for 30 min., and then asolution of 0.15 mole of sodium azide in 30 ml. of water is added dropwise at -5 to 0 C. After addition. is-complete, stirring is continued for 1 hour. The cold solution is diluted with ice water and extracted with toluene. The

toluene solution is dried with anhydrous magnesium sulfate, filtered, and heated on' a steam bathuntil the evolution of nitrogen is complete. Then, 100 ml; of methanol and 0.5 g. of Dabco (1,4-diazabicyclo[2.2.2]octane) are added and the mixture is heated, at reflux for 30 min.

Concentration of the reaction mixture yields a residue of methyl N 4 [4-(3-bromopyridyl) ]-bicyclo [2.2.2]o ct-2 en-1yl urethan.

Example 8 carboxylic acid and 300 ml. of acetone. This solution is .cooled to 5 to 0 C. and a solution of 0.11 mole of ethyl chloroformate in ml. of acetone is added dropwise, with cooling, at a rate such that the temperature does not rise above 0' C. When the addition is complete, stirring is continued for 30 min., and then a solution of 0.15 mole of sodium azide in 30 ml. of water is added dropwise at 5' to 0 C. After addition is complete, stirring is continued for 1 hour. The cold solution is diluted with ice-water and extracted with toluene. The toluene solution is dried with anhydrous magnesium sulfate, filtered, and heated on a steam bath until the evolution of nitrogen-is complete. Then, 100 ml. of methanol and 0.5 g. of Dabco? (1,4-diazabicyclo[2.2.2]octane) are added and the mixture is.heated at reflux for 30 min. Concentration of the reaction mixture .yields a residue of methyl N 4-.[2-(3-meth0xypyridyl) ]bicyclo[2.2.2]oct-2- en-l-yl urethan.

Example 10 does not rise above 0 .C. When the addition is complete,

stirring is continued for 30 min., and then a solution of dropwise at 5 to'0" C. After-addition is complete, stirring is continued for 1,houraThe.cOIdfsOIutionV-is diluted with ice water and extractedwith toluene. The toluene solution is'd'ried with anhydrous magnesium sulfate, fil- =tered, and "heated on a steam bath until the evolution of :nitrogenis complete- Then, ml. of methanol and 0.5 g.

of Dabco (1,4diazabicyc1o,[2.2.2]octane) are added and the mixture is heated at reflux 'for 30 min. Concentration of'the reaction-mixtu're yields a residue of methyl N'-- -f [3- (5'-eth'oxy'pyridyl )]bicyclo[2. 2.2]oct-2-en-l-yl urethan.. v 1 H Exam le ir j fi... f 5 a;Qf, -PY yl)bi1 cyclb.[2.2.2j]oct2-enl-carhoxylic acid and ml. of ethylene, dichloridei is add ed pvvise 50 .ml, .of thionyl chloride, with constant s H iigQRefiuxing is continued until all of the jcarh ylic ac d is dissolvdfThesolution is'allowed to cool and is evaporated; The residue is 4-(4- pyridyllbicyclo[2.2.2]oct 2-ene-l-carboxylic acid chloride as evidenced by an infrared absorption band at" 5.6;

This acid chloride is stirred WlthQG-O' g. of pulverized sodium azide-in 250 ml; of acetonitrile for 16 hours. The resultant solid'is filtered and is dissolved in a mixture of water and dichloromethane. The dichloromethane layer is separated, is dried with anhydrous magnesium sulfate, and is combined with the acetonitrile filtrate. The combined solutions are evaporated. The residue is 4-(4-pyridyl)bicyclo[2.2.2]oct-2-ene-l-carboxylic acid azide as evidenced by infrared absorption bonds at 4.67 (N;,) and 4-(4-pyridyl)bicyclo[2.2.2]octane-l-carboxylic acid, is insoluble in most solvents, but will dissolve in aqueous acid or base and may be recovered by adjusting the pH to the isoelectric point.

By substituting esters of other 4-pyridylbicyclo-[2.2.2]

at 5.86,u (CO). 5 cat 2 ene-l-carboxylic acids for 4-(4-pyridyl)-bicyclo The residue is refluxed with 200 ml. of ethanol and [2.2.2]oct-2-ene-l-carboxylic acid ethyl ester, other 4- 20 ml. of triethylamine for 16 hours. The solution is pyridylbicyclo[2.2.2]octane-l-carboxylic acids can be evaporated. The residue is chromatographed on silicic prepared. acid at pH 7 with chloroform as the eluent. Ethyl N-4- 10 EXAMPLES 22-25 (4 pyridyl)bicyclo[2.2.2]oct 2 en-l-yl urethan, M.P. 1415-1425 C, i bt i d, The procedure of Example 11 can then be repeated,

Analysis.-Ca1cd. for C H N O er ent); C, 70,56; substituting the indicated 4-pyridylbicyclo[2.2.2]octane- H, 7.40; N, 10.29. Found (percent): C, 71.51; H, 6.93; l-carboxylic acid for the 4(4-pyridyl)bicyclo[2.2.2]-oct- N, 10.28. 2-ene-l-carboxylic acid to obtain the indicated product.

Ex. Acid Alcohol Product 22 4-(4-pyridyl)bicyelo[2.2.2]octane-1- Ethanol Ethyl N-4-(p pyridyl)-bieyclo[2. .2]-

oxylica nctan-l-yl urethan, .P.190193 C- 23 4 (3-pyridyl)bicyclo[2.2.2]octane-1- ....do Ethyl N-4-(3-pyridy1)-bicyclo[2.2.2]-

carboxylic acid. octan-l-yl urethan. 24 4-(Z-pyridyl)bicyclo{2,2.2]octane-1- Methanol Methyl N-4-(2-pyridyl)-bicyclo(2.2.2]-

carboxylic acid. cctan-l-yl urethan. 4-(2-methyl-4-pyridyl)bieyclo[2.2.2]- Butanol Butyl N-t-(2-methyl-4-pyridyl)bicyclooctane-l-carboxylic acid. [2.2.21-octan-1-yl urethan.

Example 12 25 EXAMPLE 26 Example 11 is repeated using methanol instead of ethanol. The product is methyl N-4-(4-pyridyl)bicyclo- [2.2.2]oct-2-en-l-yl urethan, M.P. 163-1645 C.

Analysis.--Calcd. for C H N O (percent): C, 69.74; H, 7.02; N, 10.85. Found (percent): C, 69.66; H, 7.22; N, 10.88.

Example 13 Example 11 is repeated, substituting 0.10 mole of the indicated reactant for the 4-(4-pyridyl)bicyclo[2.2.2]oct- 2-ene carboxylic acid.

A mixture of 0.3 g. of 10% palladium on carbon, 2.72 g. (0.010 mole) of ethyl N-4-(4-pyridyl)bicyclo [2.2.2]oct-2-en-l-yl urethane, and 200 ml. of glacial acetic acid is hydrogenated in a pressure vessel at an initial pressure of 3 atm. with shaking until no more hydrogen is absorbed. The catalyst is filtered off and the glacial acetic acid is evaporated at a reduced pressure. The residue is dissolved in benzene. The solution is washed with 10% sodium bicarbonate solution, is dried with anhydrous sodium sulfate and is evaporated. The residue is then recrystallized from acetonitrile to give ethyl N-4-(4- pyridyl)bicyclo[2.2.2]octan-l-yl urethane, M.P. 190- 193 C.

Analysis.-Calcd for C H N O (percent): C, 70.04; H, 8.08; N, 10.21. Found (percent): C, 70.01; H, 7.24; N, 10.83.

I EXAMPLE 27 A solution of 16 ml. (11.6 g., 0.115 mole) of triethyl- Ex. Acid Alcohol Product 14 4-(3-pyridyl) bicyclo[2.2.2]-oct-2-ene-l- Ethanol Ethyl N4-(3-pyridyD-bicyclo[2.2.2]octcarboxylic acid. 2-en-l-yl urethan, M.P. 133.5134.5C.

15 4-(2-pyridyl)bieyclo[2.2.21-oct-2-ene-1- Butanol Butyl N4-(2-pyridyl)bicyolo[2.2'2.]octcarbox ic aci 2-en-1 yl uretha 16 4-[2-(5-ethy1pyridyl)]-bicyclo[2.2.2]oct 2-propanol 2-propyl N-4-[2-(5-ethylpyridyl)]- 2-ene-Lcarboxylic ac bicyclolZ.2.2]oct-2-en-l-yl urethan.

17 4-[6(3chloropyridyl)]-bicyclo[2.2.2]0ct- Ethanol Ethyl N4-'[5-(3-chloropyridyl)]- Z-ened-carboxylic ac" bicyclo[2.2.2]oct-2-en-1-yl urethan 18 4-[4-(3fl uoropyridyl)]-bicyclo[2.2.2]oct-2- Propanol Propyl N-4-[4*(3-fiuoropyridyl)]- ene-l-carboxylic acid. bicyclo[2.2.2]oct-2-en-yl urethan.

19 4-[2- 3-n1ethoxypyridyl)]bicyclo{2.2.2] Ethanol Ethyl N -4-[2-3-methoxypyridyl)]- oct-2-ene-1-carboxylic acid. bicyclo[2.2.2]-oct-2-en-1-yl urethan.

20 4-[3-(5-ethoxypyridyl)];bicyclo[2.2.2]oct- .do Ethyl N-4-[3- 5-ethoxypyridy1)]bicyclo- 2-ene-l-carboxylic acid.

[2.2.21-oct-2-en-1-yl urethan.

EXAMPLE 21 A solution of 100 g. of 4-(4-pyridyl)bicyclo[2.2.2]oct- Z-ene-I-carboxylic acid ethyl ester in 300 ml. of water and 100 ml. of acetic acid is shaken with 7 g. of 4% platinum on charcoal in a hydrogen atmosphere until hydrogen absorption ceases. The solution is filtered and evaporated to dryness. The residue is dissolved in Water, and the solution is made basic by adding 40% aqueous sodium hyamine in ml. of acetone is added to a stirred mixture of 22.8 g. (0.10 mole) of 4-phenylbicyclo[2.2.2]oct-2-enel-carboxylic acid and 300 ml. of acetone. This solution is cooled to 5 to 0 C. and a solution of 12.0 g. (0.11 mole) of ethyl chloroformate in 50 ml. of acetone is added dropwise, with cooling, at a rate such that the temperature does not rise above 0 C. When the addition is complete, stirring is continued for 30 minutes, and then a solution of 9.8 g. (0.15 mole) of sodium azide in 30 ml. of water is added dropwise at 5 to 0 C. After addition is complete, stirring iscontinued for 1 hour. The cold solution is diluted with ice water and is extracted with toluene. The toluene solution is dried with anhydrous magnesium sulfate, is filtered, and is heated on a steam bath until the evolution of nitrogen is complete. Then, 0.10 mole of methanol and 5 ml. of triethylamine are added and the mixture is heated at reflux for 16 hours. On cooling, the solution yields methyl N-4-phenylbicyclo- [2.2.2]oct-2-en-1-yl urethan, M.P. 141.5143 C.

9 EXAMPLES 28-55 Example 27 is repeated, substituting 0.10 mole of th indicated reactant for the 4-phenylbicyclo[2.2.2]oct-2 enel-carboxylic acid and the indicated alcohol for methanol.

Example 57 A solution of 16 m1. (11.6 g.) of triethylamine in 100 ml. of acetone is added to a stirred mixture of 23.0 g. of 4-phenylbicyclo[2.2.2]octane-l-carboxylic acid and 300 Ex. Acid Alcohol Product 28 4-phenylbieyclo[2.2.2]-oct-2-ene-1- Ethanol Ethyl N-4-phenylbicyclo-[2.2.2]oat-2- carboxylic acid. 1 en-l-yl urethan, M.P. 9798 C. (also ana ysis 29 4-phenylbicyclol2.2.2]-oct-2'ene11- Benzyl alco- Benzyl N-4-phenylbicyclo-[2.2.2]oct-2- carboxylic acid. hol. end-ylurethan, M.P. 107-l08 C.

30 i-(p-tolyl)bicyclo[2.2.2]-oct-2-ene-1- Ethanol Ethyl N4-(ptolyl)bicyclo-[2.2.2]oct-2- carboxylic acid. 1 en-l-yl urethan.

31 4-(p-ethylpheny1)bicyclo-{2.2.2]oct-2 do Ethyl N-4 (p-ethylphenyl)-bicyclo ene-l-carboxylic acid. [2.2.2]oct-2-en-1 yl urethan.

32 4-(p-fluorophenyl)bicyclo-[2.2.2]oct-2- Butano1 Butyl N-4-(p-fluorophenyl)-bicyclo ene-1-carboxylic acid. I [2.2.2]oct-2-en-1-y1 urethan.

33 4-(p-chlorophenyl)bicycl0-[2.2.2]oct-2 Isopropanol--- Isopropyl N-4-(p-ehlorophcnyl)bicyclo ene-1-carboxyhc acid.

34.- 4-(p-bromophenyl)bieyclo-[2.2.2]oct-Z ene-lcarboxylie acid.

35.. 4-(p'cyanophenyl)bicyclo[2.2.2]oct-2- ene-l-carboxylic acid.

36.- -(p-nitrophenyl)bicyclo-[2.2.2]oct-2- ene-l-carboxylic acid.

37.- 4-(p-methoyxpl1enyl)bicycle-[2.2.2]oct- 2ene-1-carboxylic acid.

38..-- 4-(p-methoxyearbonylphenyl)bicycle- [2.2.2]oct-2-ene-l-carboxylic acid.

39 4-(p-ethoxycarbonylphenyl)bicyclo- [2.2.2]oct-2-ene-l-carboxylic acid.

40 4-(m-tolyl)bicyclo[2.2.2]-oct-2-ene-1- carboxylic acid.

41 4-(n1-fiuorophenyl)bicyclo-[2.2.2]oct-2- ene l-carboxylic acid. 7

42 4-(m-hromophenyl)bicyclo-[2.2.2]oct-2- ene-l-carboxylic acid. i

43 4-(m-methoxyphenyl)bicyclo-[2.2. loct- 2-ene-1-carboxylic acid. I

44.. 4-(m-methoxycarbonylphenyl)bicyclo- [2.2.21oct-2-2ene-1-carboxylic acid.

45 4-(m-ethoxycarbonylphenyl)bicycle- [2.2.2]oct-2-ene-l-carboxylic acid.

46 4-(o-tolyl)bicycloI2.2.2]-oct-2-ene-lcarboxylic acid.

. 4 ene-l-carboxyllc acid.

48 4-(o-chlorophenyl)bicycle-[2.2.2]oct-2- ene-l-carboxylic acid.

49 4-(o-bromophenyl)bicycle-[2.2.2]oet-2- ene-l-carboxylic acid.

. i ene-l-carboxyllc acid.

51 4-2, i-dimethylphenyl)bicycle-[2.2.2]octene-l-carboxylic acid.

52... 4-(3,5dimethylphenyl)bicycle-[2.2.2]oct- 2ene-1-carboxylic acid.

53 4-(3,4'dimethoxyphenyl)bicyclo[2.2.2]

I j t oct-2-ene-l-carboxylic acid.

54 4-(3bromo-4-methoxyphenyl)bicyelo- [2.2.21oct-2-ene-l-earboxylic acid.

55 4-(3-nitro-4-methoxy-phenyl)bicyelo- [2.2.2]oct-2-ene-1-carboxylic acid.

Example 5 6 V A solution of 40 g.- of ethyl 4-phenylbicyclo[2.2.21oct- 2'-en'e-l-'carboxylate in 100 ml. of ethanol is hydrogenated [2.2.2]oct-2-en-l-yl urethan.

V 1-octan0l.... n-O ctyl N -4-(p-bromophcnyl)bicyclo [2.2.2]oct-2-en-2-yl urethan. Propanol Propyl N4-(p-cyanophcnyl)bicyclo [2.2.2]oct-2-en-1-yl urethan. 2-metlioxy eth- Z-Methoxyethyl N-4-(p-nitrophenyl) an bicyelo[2.2.2]oct-2-cn-1-yl urethan. Ethanol Ethyl N-4-(p-methoxyphenyl)bicyclo [2.2.2]oct-2-en-1-yl urethan. MethanoL. Methyl N-4-(p-methoxy-carbonylphenyl) I bicyclo[2.2.2]oct-2-en-l-yl urethan. Ethanol Ethyl N-4-(pethoxycarbonyl-phenyl) I bicyclo[2.2.2]cct-2-en-1-yl urethan.

. Q-dimcthyl- 2-Dimethylaminoethyl-N- i-(m-tolyl) amilno ethbicyelo[2.2.2]oct-2-en-1-yl urethan. ano

2pyrrolidyl .Z-Pyrrolidylethyl N-4-(m-fluorophenyl) ethanol. bicyclo[2.2.2]oct-2-en-1-yl urethan.

- Hexanol. Hexyl N-4-(m-bromophenyl)bicyclo [2.2.2]oct-2-en-l-yl urethan.

Heptanol Heptyl N-4-(m-methoxyphenyl)blcyclo [2.2.2]oct-2-en-l-yl urethan.

Propanol.-- Propyl N-4'-(m-methoxycarbonylphenyl) .bicyclo[2.2.2]oct-2-en-1-yl urethan. 2 Butanol. 2 -Butyl N-4-(m-cthoxycarbonylphenyl) bicycle[2.2.2]oct-2-en-1-yl urethan. Ethanol Ethyl N -4-(o-tolyl)bicyclo[2.2.2]oct-2-enl-yl urethan. Methanol Methyl N-4-(o-fluorophenyl) blcyclo [2.2.2]oct-2-en-l-yl urethan. do Methyl N-4-(o-chlorophenyl)bicyolo [2.2.2]oet-2-en-1-yl urethan. Propanol. Propyl N-4-(o-bromophenyl)bicycle [2.2.2]oct-2-en-1-yl urethan.

2-rncth0xy 2-Methoxyethyl N-i-(o-nitrophenyl) ethanol. bicyclo[2.2.2]oct-2-cn-1-yl urethan.

Butanol Butyl N -4-(2,4-dimethylphenyl) blcyclo [2.2.2]oct-en-yl urethan.

Ethanol Ethyl N-4-(3-5,dimethylphenyl)bicyclo [2.2.2]oct-2en-1-yl urethan.

Methanol Ethyl N-4-(3,4-dimethoxyphenyl)bleyclo [2.2.2]octr2-en-1-ylurethan. M-P- 123.5-124 C.

Hexanol Hexyl N-4-(3-bromo4anethoxyphenyl) bicyclo [2.2.2]oct-2'en-1-yl urethan.

Methanol Methyl N-4(3-nitro-4-methoxyphenyl) bicyclo[2.2.2]oct-2 en-l-yl urethan.

ml. of acetone. This solution is cooled to -5 to 0 C. and a solution of 12.0 g. of ethyl chloroformate in 50 ml. of acetone is added dropwise, with cooling, at a rate such that the temperature does not rise above 0 C. When the addition is complete, stirring is continued for 30 minutes, and then a solution of 9.8 g. of sodium azide for l6'hour's at atmospheric pressure. A-solution of 0.2 M chlor'oplatinic acid'initially is added to the solution until uptake of hydrogen commences. The catalyst is filtered oif and'the solvent is evaporated. The residue is recrystallized from methanol to give 22.2 g. of ethyl4-phenylbicyclo [2.2.2]octane-l-carboxylate, M.P. 6869 C.

m'ixtur'e'of 11 'g. of' ethyl 4-phenylbicyclo[2.2.2] octane-l-carboxylate and 1000 ml. of 2 N sodium hydroxide solution is refluxed for '16 hours with stirring. The mixture is allowed to cool slightly and is acidified with concentrated HCl' so that the temperature is held 'at 80- 100"C. Cooling the acidified solution gives 9.0 g. of 4- phenylbicyclo[2.2.2] octan-l-carboxylic acid, which can be purified by recrystallization from acetic acid to give crystals, 277-279 C. A sample purified for analysis melts at282-284 C. Y i

Analysis-Called. for C H O (percent): C, 78.23; H, 7.88; mol. wt., 230. Found (percent): C, 77.76; H, 7.71; mol wt., 226.

in 30 ml. of water is addeddropwise at 5 to 0 C. After addition is'complete, stirring'is continued for 1 hour. The cold solution is diluted with ice water and is extracted with toluene. The toluene solution is dried with anhydrous magnesium sulfate, is filtered, and is heated on a steam bath until the evolution of nitrogen is complete. Then, 0.10 mole=of ethanol and 5 ml. of triethylamine are added and the mixture is heated at reflux for 16 hours. On cooling, the solution yields ethyl N-4-phenylbicyclo [2.2.2]octane-1-yl urethan, M.P. 1101l1.C.

' Examples 58-80 By substitutingv alower alkyl ester of'the desired 4- arylbicyclo[2.2.2]oct-2-ene-1carb0xylic acid for the ethyl 4-phenylbicyclo[2.2. 2]oct-2-ene-1-carboxylate in Example 56 and then substituting the resultant arylbicyclo[2.2.2] octane-lcarboxylic acid for the 4-phenylbicyclo[2.2.2] octane-l-carboxylic acid in Example 57, and by using the indicated alcohol, the indicated urethans may be prepared. r i

Ex. Acid Alcohol Product 57 4-o-to1ylbicyclo[2.2.2]-octane-1-carboxyl- Methanol Methyl N-4-o-tolylbicyclo-[2.2.2]octane ic acid. l-yl urethan.

58 4-m-tolylbicyclo[2.2.21octane-1-carboxyl- Propanol Propyl N -4-n1-toly1bicyclo[2.2.2]octan-1- to acid. yl urethan.

59 4-p-tiollylbicyclo[2.2.2]octane-l-carboxylic Octanol Octylfllf-tp-tolylbicyclofi.2.2]octan-1-yl ac ure an.

61 4-p-ethylphenylbicyclo[2.2.2]octane-ll-Propanol. 2-propyl N-4-p-ethy1pheny1bicyclo[2.2.2]

carboxyllc acid. octan-l-yl urethan.

62.. 4-(2,4-dimethyl)phenylbicyclo[2.2.21oc- Ethanol..- Ethyl N-4-2,4-dimethylbicyclo[22.2]

tane-l carboxylic acid. octan-l-yl urethan.

63.- 4-(3,o-dimethyl)phenylbicyclo[2.2.21oc- Hexanol Hexyl N-4-(3,5-dirnothylphenylbicyclo tane-l-carboxylic acid [2.2.2]octan-1-yl urethan.

64 4-(2,6-dimethyl)phenylbicyclo[2.2.21oc- Propanol Propyl N-4-(2,fi-dimethylphenylbicyclo tanal-carboxylic acid. [2.2.2]octan-i-yl urethan.

65...- 4-(4-ethyl-2-methylphenyl)bicyclo[22.2] Methanol Methyl N4-(4-ethyl-2-methylphenyl)bioctane-l-carboxylic acid. cyclo[2.2.2]octan-1-yl urethan.

66 4-(2,4-diethylphenyl)bicyclo[2.2.2]oc- Ethanol Ethyl N-4-(2,4-diethylphenyl) bicyclo tane-l-carboxylic acid. [2.2.2]octan-l-yl urethan.

67 4-(p-fluorophenyl)bicyclo[2.2.2]octane Pentanol Pentyl N-4-(p-fluorophenylbicyclo[22.2]

l-carboxylic acid. octau-l-yl urethan.

68 4-(p-chlorophenyl)bicyclo-[2.2.2]octane Butanol Butyl N-4-p-chlorophenylbicyclo[2.2.2]

l-carboxy a octan-l-yl urethan.

69 4-(p-bromophenylbicycloIZ.2.2]octaue-1- Heptanol Heptyl N-4-p-brornophenylbieyclo[2.2.2]

carboxylic acid. octau-l-yl urethan.

70 4-(o-chlorophenyl)bicyclo[2.2.2]octane-i Allyl alcohol Allyl N- i-o-chlorophenylbicyclo[2.2.210ecarboxylic acid. tan-I-yl urethan.

71 4-(o-bromopheny1)bicyclo[2.2.2]octane-1- 2-methoxy 2-Methoxyethyl N-4-o-bromophenylbicycarboxylic acid. clo[2.2.2]octan-1-yl urethan.

72 4-(o-chlorophenyl)bicyclo[2.2.2]octane-1- Methanol Methyl N-to-chlorophenylbicyclo[2.2.2]

carboxylic acid. octane-l-yl urethan.

73 4-(p-bromophenyl)bicyclo[2.2.2]octaue-1- Ethanol Ethyl N -4-p-bromophenylbicyclo[2.2.2]

carboxylic acidoctane-l-yl urethan.

74 4- p-methoxyphenyl)bicyclo[2.2.2]oc- -do Ethyl N-4-p-methoxy%1enylbicyclo[2.2.]

tane-l-carboxylic acid. octane-l-yl urethan, .P 108.5109C.

75 4-(p-ethoxyphenyl)bicyclo[2.2.2]octane- 2-butano1 2-buty1 N -4-p-ethoxypheuylbicyclo[2.2.2]

l-carboxylic acid. l-yl urethan.

76 4-(2,4-difluorophenyl) bicyclo[2.2.2]oc- 2-propanol 2-propyi N4-(2,4-difiuorophenylbicyclo tane-l-oarboxylic acid. [2.2.2]octane-1-yl urethan.

77 4-(2-chloro4-fiuorophenyl) bicyclo[2.2.2] Butanol Butyi N4-(2-chloro-4-fiuorophenylbicyoctane-l-carboxylic acid. clo[2.2.2]octane-1-yl urethan.

7S 4(2,4-dimethoxyphenyl)bicyclo[2.2.2] 2-pyrr0lidyl 2-pyrroiidylethyl N-4-(2,4-dimethoxyoctane-l-carboxylic acid. ethanol. phenylbicyclo[2.2.2]octane-1-yl urethan.

79 4-(3,4-dimethoxyphenyl)bicyclo[2.2.2] Ethanol Ethyl N -4-(3,4-dimethoxyphenylbicyclo octane-l-carboxylic acid. [2.2.2]ootane-i-yl urethan.

80 4-(2,4-dinitropheny1)-bicyclo[2.2.2]ocdo Ethyl N-4-(2,4-dinitrophenylbicyclo tane-l-carboxylic acid. [2.2.2]octane-1-yl urethan.

Example 81 Example 87 A container of a material resistant to hydrogen fluoride attack (as for example, platinum, Hastelloy steel, or polyethylene) is cooled with solid carbon dioxide and acetone and is charged with about 50 ml. of anhydrous hydrogen fluoride. The liquid is stirred and 11.8 g. (0.0432 mole) of ethyl N-4-phenylbicyclo[2.2.2]octanl-yl urethan is added. Then 2 ml. (3.00 g., 0.043 mole) of fuming nitric acid (90%) is added slowly. The cooling bath is removed and the solution is allowed to stand for 16 hours. The hydrogen fluoride is evaporated, the residue is dissolved in dichloromethane and is washed with sodium carbonate solution. The dichloromethane solution is dried with anhydrous magnesium sulfate and evaporated. The residue is primarily ethyl N-4-(p-nitropheny1)bicyclo[2.2.2]octan-1-yl urethan.

Example 82 Hydrazine hydrate ml.) is dropped into a suspension of 1 teaspoon of Raney Nickel in a solution of 0.040 mole of ethyl N-4-(p-nitrophenyl)bicyclo[2.2.2] oct-2-en-l-yl urethan in 500 ml. of ethanol at 70 C. When the addition is complete, the mixture is cooled and the catalyst is filtered oil. The filtrate is evaporated to give ethyl N-4-(p-aminophenyl)bicyclo[2.2.2]0ct-2-en-yl urethan.

Examples 83-86 The procedure of Example 82 is repeated substituting 0.040 mole of the indicated reactant for the ethyl N-4- (p nitrophenyl)bicyclo[2.2.2]oct 2 en 1 yl urethan of Example 82.

A 28.8 g. (0.10 mole) quantity of ethyl N-4-(p-aminophenyl)bicyclo[2.2.2]octan-1-yl urethan is heated with 0.50 mole of formic acid and 0.22 mole of formaldehyde on the steam bath for 2 to 4 hours after evolution of gas has ceased. The reaction mixture is cooled and is diluted with ml. (2 moles) 50% of aqueous sodium hydroxide. The basic solution is extracted with ether, which after drying over sodium sulfate, is evaporated to yield ethyl N 4 (p dimethylaminophenyl)bicyclo[2.2.2] octan-yl urethan.

Example 88 A 0.5 g. quantity of 10% Pd on charcoal is added to a solution of 40 g. of methyl N-4-(m-nitrophenyl)bicyclo[2.2.2]oct-2-en-1-yl urethan in 200 ml. of ethanol. The mixture is shaken under 50 lb. per sq. in. of hydrogen for 16 hours. The catalyst is filtered oif and the solvent is evaporated. The residue is methyl N-4-(m-aminophenyl)bicyclo[2.2.2]octan-1-yl urethan.

The compounds for use in the method of this invention can be administered for antidepressant effect according to this invention by any suitable means. For example, administration can be parenteral, that is subcutaneous,- intravenous, intramuscular, or intraperitoneal. Alterna-' tively or concurrently, administration can be by the oral route.

The dosage administered will be dependent upon age, health and weight of the recipient, the kind of concurrent treatment if any, frequency of treatment, and intensity of the antidepressant response desired. Generally, a daily dosage of active ingredient compound will be from about 0.01 to 10 and preferably 0.05 to 2.5 milligrams per kilogram per day is effective to obtain the desired result.

Ethyl, N 4 phenylbicyclo[2.2.2] oct 2 ene 1 yl urethan, a compound for this invention, strongly indicates antidepressant activity, as is established when said compound, administered orally to mice at a dose of 5.0 mg. per kg. of body weight, successfully demonstrates protection against tetrabenazine-induced sedation.

The active ingredient for this invention can be employed in useful compositions according to the present v:invention in such dosage forms as tablets,.capsules, .pow-

der packets, or liquid solutions, suspensions, or elixir s,

for oral administration or liquid solutions for parenteral use, and in certain cases,,suspensions for parenteral use. In such compositions the" active ingredient will ordinarily always be present in an amount of at least 0.01% by weight based on the total weight of the composition and not more than 90% by weight.

Besides the active ingredient of this invention the composition willfcontain a solid orliquid non-toxic pharmaceut ical carrier for the active ingredient.

In one'iembodiment of, a pharmaceutical composition of 1n v ent ion, the solid carier is a capsulewhich can be he ordinary gelatin type. In the capsule willfbe lf fom aboijt l' 50% by weight of an N-4-arylbicyclo [2.2'.2]'o'ct'an or oct-2-en-1-y1'urethan for this invention and 99,- 50.% of a carrier; In" another embodiment, the

active ingredient is table ted withv or withoutadjuvants. In yet another embodiment, the active ingredient is put into powder packets and employed.- These capsules, tablets, and powders -will generally constitute from about 0.5% to about 95% and preferably from 1% to 50% by weight of active ingredient. These .dosage forms preferably contain from about 0.5 to about 250 milligrams of active ingredient, with from about'l milligram to about '50'finilligram's most preferred.

-*f --The pharmaceutical carirer can, as previously indicated beas'te'rile liquid such as-water andoils, including those: ofpet' r oleum, animal, vegetable or-synthetic origin, for';exani'ple peanut oil, soybean oil, mineral oil sesame oih' and "the like. In general, water, "saline, aqueous dextrose (gl uc ose) and related sugar solutions and" glycols such as prepyiene glycol or polyethylene glycolsare 59. .Suitablepharmaceutical carriers are-described in Remingtons Pharmaceutical Sciences by W. Martin, a

well-known reference text in this field.

, In addition to the.ieiiemplary 'illiistrations above, the following examples-further explainone aspect of the presgr t invention: M g -I y A large number of unit "capsules areprepared fororal administration by .filling standard two-piece. hard gelatin capsules weighing about 25 milligrams each with 50 milligrams of powdered ethyl, N -4-phenylbicyclo[2.2.2]-oct 2 ene-l-yl urethan, 125 milligrams of lactose and' l milligram of Cab-o-sil finely divided silica.

Example 90 A large number of unit capsules are prepared for oral administration by filling soft gelatin capsules with a solution of benzyl N-4-phenylbicyclo[2.2.2]oct-2-ene-1-yl urethan in mineral oil.

Example 91 A large number of tablets are prepared by conventional procedures so that the dosage unit is 10 milligrams of active ingredient, 5 milligrams of gelatin, 1.5 milligrams of magnesium stearate and 100 milligrams of lactose. Slow release tablets can also be used, by applying appropriate coatings.

. A large variety of compositions according to this invention can thus readily be made by substituting other compounds for this invention, and including specifically but not li'mted to compounds for this invention that have specifically been named hereinbefore. The compounds will be used in the amounts indicated in accordance with procedures well known and described in the Martin text mentioned above.

I claim:

- 1. An pharmaceutical formulation selected from the group consisting of a tablet, capsule, powder packet, syrup, suspension, elixir and parenteral solution comprising an antidepressant efiective amount of a compound selected from the group represented by the formulae:

where R is alkyl containing from 1 through 8 carbons,

ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl contains from 1 through 4 carbons, cyano, alkoxy containing from 1 through 4 carbons, alkoxy carbonyl where the alkyl contains from 1 through 2 carbons on trifluoromethyl;

N NHCOOR where R is alkyl containing from 1 through 8 carbons, ethylpyrrolidinyl, or phenyl; and R is hydrogen,methyl, ethyl, chlorine, bromine fluorine, nitro, amino, dialkylam-ino where each alkyl contains'froml through 4 carbons, cyano, alkoxycarbonyl where the alkyl containsfrom 1 through 2 carbons, or trifluoromethyl.

3. A pharmaceutical formulation of claim 1 wherein the active ingredient is a compound of the formula N NHCOOR where R is alkyl containing from 1 through 8 carbons, ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl contains from 1 through 4 carbons, cyano, alkoxy containing from 1 through 4 carbons, alkoxy carbonyl where the alkyl contains from 1. through 2 carbons or trifluoromethyl.

mula

N NHC R where R is alkyl containing from 1 through 8 carbons, ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl contains from 1 through 4 carbons, cyano, alkoxy containing from 1 through 4 carbons, alkoxy carbonyl where the alkyl contains from 1 through 2 carbons or trifluoromethyl; with a non-toxic anion derived from the acids of the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, citric acid and carbonic acid.

5. A pharmaceutical formulation of claim 1 wherein the active ingredient is a salt of a compound of the N NHC OOR where R is alkyl containing from 1 through 8 carbons, ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl contains from 1 through 4 carbons, cyano, alkoxy containing from 1 through 4 carbons, alkoxy carbonyl where the alkyl contains from 1 through 2 carbons or trifluoromethyl; with a non-toxic anion derived from the acids of the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, citric acid and carbonic acid.

6. A method for producing an anti-depressant effect in a warm-blooded animal comprising administering to said animal an anti-depressant effective amount of a compound selected from the group consisting of a compound of the formulae:

NHCOOR where R is alkyl containing fiom 1 through 8 carbons,

ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl contains from 1 through -4 carbons, cyano, alkoxy containing from 1 through 4 carbons,

alkoxycarbonyl where the alkyl contains from 1 through 2 carbons, or trifluoromethyl;

A NHCOOR N NHCOOR where R is alkyl containing from 1 through 8 carbons, ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialkylamino where each alkyl contains from 1 through 4 carbons, cyano, alkoxy containing from 1 through 4 carbons, alkoxy carbonyl where the alkyl contains from 1 through 2 carbons or trifluoromethyl.

8. The method of claim 6 wherein the compound administered is a compound of the formula;

where R is alkyl containing from 1 through 8 carbons, ethylpyrrolidinyl, or phenyl; and R is hydrogen, methyl, ethyl, chlorine, bromine, fluorine, nitro, amino, dialk ylamino where each alkyl contains from 1 through 4 carbons, cyano, alkoxy containing from 1 through 4 carbons, alkoxy carbonyl where the alkyl contains from 1 through 2 carbons or trifluoromethyl.

References Cited UNITED STATES PATENTS- 3,337,571 8/1967 Gregory 260-295 ALBERT T. MEYERS, Primary Examiner S. J. FRIEDMAN, Assistant Examiner US. Cl. X.R. 424-309 ing? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION 5. 5 7, 957 Dated A aril 21, 1970 Patent No.

Inventor(s/I Paul E. Aldrich It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

in In Claim 1, line 29 of Column 1 1, the term "on" should read or line 37 of Column l t, the term "R( should read R In Claim 2, line 58 of Column l t, the following statement should be inserted after the word "cyano": alkoxy containing from 1 through 4 carbons,

In Claim 6, Column 15, the structural formula should be identified with the legend (A) in the margin and at Column 16, the structural formula should be identified with the legend (B) in the margin.

.SEAL) Attcst:

Edward M. Fletcher, Ir. I

ffi LLIA E- SGHUYL JR Anestmg 0 cer ioner of Patents 

